The search for a systemic agent that inhibits epidermal cell replication without systemic toxicity and is safe and effective in clearing generalized psoriasis has resulted in the development of an approach that is termed photochemotherapy. Oral methoxsalen (8-methoxypsoralen or 8-MOP) followed by exposures to a measured dose of UV-A radiation emitted by a specially designed high-intensity, longwave ultraviolet light source (UV-A or 320-400 nm with peak emission at 350-360 nm) has been used quite successfully to treat over 300 patients with generalized psoriasis. Nearly 95% of patients had complete clearing of their psoriasis after an average of 14 to 16 treatments. Oral administration of the photoactive drug 8-methoxypsoralen to guinea pigs and subseqent exposure of skin with UV-A (320-400 nm) results in significant inhibition of DNA biosynthesis. The improvement or clearance of psoriasis, a disease associated with cellular proliferation in the epidermis, appears to involve the inhibition of DNA synthesis with oral 8-MOP and subsequent UV-A irradiation. The kinetics of absorption and excretion of psoralens (psoralen, trimethylpsoralen and 8-methoxypsoralen) have been examined in the urine and blood specimens of mice and human subjects. The characteristics of erythema reactions (energy requirements in mj/cm2 or J/cm2, time of onset, duration, etc.) induced by UV-C (lambda less than 280 nm), UV-B (290-320 nm), UV-A (320-400 nm) and UV-A plus 8-methoxypsoralen were studied. The metabolic alterations of orally administered psoralens (psoralen, 4, 5', 8-trimethylpsoralen) have been examined in mice and in human volunteers. One of the major fluorescent metabolites of trimethylpsoralen has been isolated, crystallized and identified as dimethyl carboxypsoralen (DMeCP) with molecular weight of 258. A minor metabolite appears to be a hydroxylated derivative of DMeCP with molecular weight of 274. A DMeCP-like metabolite is also present in the urine of patients receiving oral trimethylpsoralen. The metabolism of psoralen and trimethyl-psoralen also involves hydroxylation and conversion to glucuronides.